CA1327798C - Imidazoquinoxaline compounds and their preparation and use - Google Patents
Imidazoquinoxaline compounds and their preparation and useInfo
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- CA1327798C CA1327798C CA000602682A CA602682A CA1327798C CA 1327798 C CA1327798 C CA 1327798C CA 000602682 A CA000602682 A CA 000602682A CA 602682 A CA602682 A CA 602682A CA 1327798 C CA1327798 C CA 1327798C
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
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Abstract
ABSTRACT
New imidazoquinoxaline compounds having the general formula wherein R3 is , , or CO2R' wherein R' is C1-6-alkyl, which may be straight or branched, C3-7-cyclo-alkyl or phenyl; and R4 is hydrogen or C1-6-alkyl; and 5-N-oxides thereof.
The compounds are useful in psychopharmaceutical preparati-ons as anticonvulsants, anxiolytics, hypnotics, and in improving the cognitive function of the brain of mammals.
New imidazoquinoxaline compounds having the general formula wherein R3 is , , or CO2R' wherein R' is C1-6-alkyl, which may be straight or branched, C3-7-cyclo-alkyl or phenyl; and R4 is hydrogen or C1-6-alkyl; and 5-N-oxides thereof.
The compounds are useful in psychopharmaceutical preparati-ons as anticonvulsants, anxiolytics, hypnotics, and in improving the cognitive function of the brain of mammals.
Description
132779~
Imidazoquinoxaline Compounds and Their Preparation and Use.
The present invention relates to therapeutically active imi-dazoquinoxaline compounds, a method of preparing the same, pharmaceutical compositions comprising the compounds, and to methods of treating therewith. The novel compounds are useful in psychopharmaceutical applications, e.g., in the treatment of central nervous system ailments, for example, as anticonvulsants or anxiolytics.
It is well known (Squires, R.F. and Braestrup, C. in Nature (London) 266 (1977) 732-734) that specific sites in the cen-tral nervous systems of vertebrates exhibit a high specific affinity for bindlng 1,4- and 1,5-benzodiazeplnes. These sites are called benzodiazepine receptors.
.
It has now been found that members of a novel group of imi-dazoquinoxaline compounds have strong affinity for the ben-~, zodiazepine receptors which make them useful in psychophar-maceutlcal preparations.
According~y, lt is an ob~ect of the lnventlon to provlde such novel imidazoquinoxaline compounds.
!~ 25 The imidazoguinoxaline compounds of the invention have the i general formula I
~ R3 (I) wherein !; R is ~ ~ or CO2R' .;
,:
,~
., .
Imidazoquinoxaline Compounds and Their Preparation and Use.
The present invention relates to therapeutically active imi-dazoquinoxaline compounds, a method of preparing the same, pharmaceutical compositions comprising the compounds, and to methods of treating therewith. The novel compounds are useful in psychopharmaceutical applications, e.g., in the treatment of central nervous system ailments, for example, as anticonvulsants or anxiolytics.
It is well known (Squires, R.F. and Braestrup, C. in Nature (London) 266 (1977) 732-734) that specific sites in the cen-tral nervous systems of vertebrates exhibit a high specific affinity for bindlng 1,4- and 1,5-benzodiazeplnes. These sites are called benzodiazepine receptors.
.
It has now been found that members of a novel group of imi-dazoquinoxaline compounds have strong affinity for the ben-~, zodiazepine receptors which make them useful in psychophar-maceutlcal preparations.
According~y, lt is an ob~ect of the lnventlon to provlde such novel imidazoquinoxaline compounds.
!~ 25 The imidazoguinoxaline compounds of the invention have the i general formula I
~ R3 (I) wherein !; R is ~ ~ or CO2R' .;
,:
,~
., .
2 1327798 ~
wherein R' is C1 6-alkyl, which may be straight or branched, C3 7-cyclo-a kyl or phenyl; and R is hydrogen or Cl 6-alkyl; and 5-N-oxides thereof.
The invention also relates to a method of preparing the above mentioned compounds. This method comprises:
a) reacting a compound of formula II
~ ~ R4 (II) wherein R4 has the meaning set forth above and wherein Y is a leaving group, wlth a compound having the formula III
CN - CH2 - R3 (III) wherein R3 has the meaning set forth above, to form a com-pound of the lnvention, or b) reacting a reactive derlvative of a compound havlng the general formula IV
~ ~ C02H (IV) wherein R4 has the meaning set forth above, with a compound having the general formula V
R'- C(=NOH)NH2 (V) wherein R ' has the meaning set forth above to form a compound of the general formula I wherein R is ~0~
~ ~.
wherein R' has the meaning set forth above.
The leaving group, Y, may be any suitable leaving group and, for example, those disclosed in U.S. Patents 4,031,079 or 4,359,420, for example, halogen, alkylthio, e.g., methylthio, aralkylthio, N-nitrosoalkylamino, alkoxy, mercapto, -OP(O)(OR)2 wherein R is lower-alkyl or -OP(O)(NR`R `) where-in R` and R`` each represents lower-alkyl or phenyl, or to-gether with the nitrogen atom to which they are attached re-present a heterocyclic radical such as morpholino, pyrrolidino, piperidino, or methylpiperazino. The reaction is preferably carried out under alkaline conditions, i.e., in the presence of a base, and among bases alkali metal, e.g., potassium or sodium, al~oxldes or hydrldes are pre-ferred. The reactlon is preferably conducted in the presence of an organic solvent which is nonreactive with the reac-tants and products of reaction under the conditlons of reac-tlon, especially an anhydrous solvent and preferably an an-hydrous aprotio solvent such as dlmethylformamlde (DMF) or the like. The temperature range employed may be any range suitable for the reaction to proceed at a reasonable rate and without undue delay or decomposition and a range from a minus forty (-40) degrees Celsius to about room temperature is accordingly usually particularly suitable.
The starting materials may be prepared from commercially available organic compounds and by using well known synthe-tic method8 and as described in Synthesis, Vol. 10, pp.681-682.
4 1327798 ' .
The pharmaceutical properties of the compounds of the inven-tion can be illustrated by determining their capability for displacing radioactive labelled flunitrazepam from benzodi-azepine receptors.
The displacement activity of the compounds of the invention may be found by determining the ED50 value. The ED50 value represents the dose (mg/kg) of a test substance which causes the specific binding of flunitrazepam to benzodiazepine re-ceptors in a living brain to be reduced to 50~ of the con-trol value.
Such an in vivo test is carried out as follows:
Princi~le. Twenty mlnutes after a dose of H-flunitrazepam (3H-FNM) (200 ~Ci/kg, l.v.) the amount of specific 3H-FNM
binding to brain benzodiazepine receptors has reached its maximal value. This specific binding of 3H-FNM can be part-ly or completely prevented by simultaneous or prior adminl-stration of pharmacologically active benzodiazepines and bysome benzodlazepine-like agents (Chang and Snyder, Eur.J.
Pharmacol. 48, 212-218 (1978)).
Test procedure. Suspenslons of test substances (2 mg/ml) are prepared in 5~ Duphasol-X (TM Duphar, castor oil-ethylene oxlde derivative for emulsifying and solubilizing oil and other water-insoluble substances) by sonlficatlon for 10 min using a Bran80n B15 microtip ultrasonifier (setting 7).
Groups of three miae (female, MMR, 18-22 grams) are inJected with the test sUb8tance at 100 mg/kg intraperitoneally. Fif-teen minute9 after test substance administration the mice are challenged with 4 ~Ci intravenously of 3H-FNM (70-90 Ci/mole) ln 200 ~1 physiological saline. ~wenty minutes after 3H-FNM admlnistratlon mlce are sacrificed by decapita-tlon, the forebralns rapldly excised (within 30 sec) andhomogenized in 12 ml of lcecold 25 mM KH2P04, pH 7.1, using an Ultra-Turrax homogenizer fitted with an N 10 shaft. Two .
aliquots of 1 ml are immedlately filtered through Whatman GF/C glassfibre filters and washed with 2 x 5 ml af the above mentioned buffer. The amounts of radioactivity on the filters are determined by conventional scintillation count-ing. One group of untreated mice serves as control. One tothree mice are inJected with 25 ,ug/kg clonazepam i.p. 30 minutes before H-FMM to determine the amount of non-speci-fic H-FMM binding, which should be between 8-15~ of total binding. When doses of 100 mg/kg inhibit more than 50% of specific H-flunitrazepam binding; test substances are admi-nistered in doses, which are factors of 3.16 times lower than 100 mg/kg. The ED50 for a test substance ls defined as that dose which inhibits 50% of specific H-FNM binding.
Specific binding is the amount of binding in controls mlnus the amount binding ln clonazepam-treated mice.
Results. The ED50 value is determined from dose response curves. If only one dose of test substance is administered the ED50 value is calculated as follows, provided that the inhlbltlon of specific binding is within the range of 25-75%:
ED50 ' (admini5tered dose) x mg/kg r CO
_ - 1 ~ Cx where CO is specific blnding ln controls and Cx ls speclfic blnding in mice treated wlth test substance.
Test results obtained by testing some compounds of the in-ventlon will appear from the following table I.
, TABLE 1, CompoundED50 (mg/kg) 8 1.8 7 1.3 3.5 The compound of the invention, together with a conventional adjuvant, carrier, or diluent, and if desired in the form of a pharmaceutically-acceptable acid addltion salt thereof, may be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or fllled capsules, or llquids, such as solutions, suspensions, emulsions, elixirs, or cap-sules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterlle ln~ectable solutlons for parenteral (including subcutaneous) use. Such pharmaceutlcal compositions and unlt dosage forms thereof may comprise conventional ingre-dients in conventional proportions, with or without additio-nal active compounds or principles, and such unit dosage forms may contain any suitable effective central nervous system ailment alleviating amount of the active ingredient commensurate with the intended daily dosage range to be employed. Tablets containlng one (1) milligram of active ingredient or, more broadly, one (1) to thirty (30) milli-grams, per tablet, are aocordlngly sultable representativeunit dosage forms.
The oompounds of this invention can thu~ be used for the formulation of pharmaceutical preparations, e.g., for oral and parenteral administratlon to mammals including humans, ln accordance with conventional methods of galenic pharmacy.
,. ~ .~ .
, . . . .
..
.
.
Conventional excipients are such pharmaceutically acceptable organic or inorganic carrier substances suitable for paren-teral or oral application which do not deleteriously react with the active compound.
Examples of such carriers are water, salt solutions, alco-hols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose and polyvinylpyrrolidone.
The pharmaceutical preparations can be sterilized and mixed, if desired, with auxilliary agents, such as lubricants, pre-1~ servatives, stabilizers, wettlng agents, emulsifiers, saltfor influenclng osmotic pressure, buffers and/or coloring substances and the like, which do not deleteriously react with the active compound.
For parenteral application, particularly suitable are in~ec-table solutions or suspensions, prefarably aqueous solutions with the actlve compound dissolved in polyhydroxylated cas-tor oil.
Ampoules are convenient unit dosage forms.
For oral applicatlon, particularly suitable are tablets, dragees, or capsule~ having talc and/or a carbohydrate car-rler or binder or the like, the carrier preferably being lactose and/or corn starch and/or potato starch. A syrup, elixir or llke can be used when a sweetened vehicle can be employed. Generally, as to broader ranges, the compounds of the lnvention are dlspensed ln unit dosage form comprising 0.05-100 mg in a pharmaceutically-acceptable carrier per unlt dosage.
A typical tablet which may be prepared by conventional tab-letting techniques contains:
Active compound 1.0 mg Lactosum 67.8 mg Ph.Eur.
Avicel~ 31.4 mg Amberlite~ IRP 8~1.0 mg Magnesii stearas 0.25 mg Ph.Eur.
Due to their high degree of affinity for the benzodiazepin receptors, the compounds of the invention are extremely use-ful in the treatment of eentral nervous system ailments or disorders, when administered in an amount effective for the alleviation, amelioration, or elimlnation thereof. The im-15 portant CNS aativity of the compounds of the invention in- -cludes both anticonvulsant and anxiolytic actlvities along with a low toxielty, together presenting a most favorable therapeutie lndex. The eompounds of the invention may accord-ingly be administered to a sub~ect, e.g., a living animal body, includlng a human, in need of the same for the treat-ment, alleviatlon, amelioration, or elimination of an indi-cation, associated with the central nervous system and the socalled benzodiazepin receptors, which re~ulres sueh psyeho-pharmaeeutieal treatment, e.g., especlally eonvulsion and/or anxiety states, if desired in the form of a pharmaeeutieally-aeeeptable aoid addition salt thereof (such as the hydro-bromide, hydroehloride, or sulfate, in any event prepared in the usual or eonventional manner, e.g., evaporation to dryness of the free base in solution together with the aeid), ordlnarlly eoneurrently, slmultaneously, or together with a pharmaeeutieally-aeceptable earrier or diluent, espeelally and preferably in the form of a pharmaceutical composition thereof, whether by oral, reetal, or parenteral (lneludlng subeutaneous) route, ln an effective psychopharmaceutieal eentral nervous system allment allevlating amount, e.g., an antleonvulsant and/or anxiolytie amount, and in any event ~' an amount which is effective for the alleviation of such a central nervous system ailment due to their benzodiazepine receptor affinity. Suitable dosage ranges are 1-200 milli-grams daily, 1-100 milligrams daily, and especlally 1-30 milligrams daily, depending as usual upon the exact mode of administration, form in which administered, the indication toward which the administration is directed, the sub~ect involved and the body weight of the subject involved, and ; the preference and experience of the physician or veteri-narian in charge.
The invention will now be described in further detail with reference to the following examples:
Ethyl 4-methyl-lmidazo[1,5-a]quinoxaline-3-carboxylate 3-Methyl-2-~ulnoxalinol (2.84 g, 18 mmol) was dlssolved ln dry DMF (40 ml) and charged wlth sodium hydride (55~ oil dispersion, 1.0 g, 23 mmol). The resulting solution was cooled under nitrogen to -20C, whereafter chlorodiethyl-phosphate (3.3 ml, 23 mmol) was added. The reaction mixturewas allowed to reach room temperature, and was then added a -30C cold solution of ethyl isocyanoacetate (2.6 g, 23 mmol) and potassium t-butoxide (2.6 g, 23 mmol) in dry DMF (25 ml).
The mixture was stirred for 45 min. at ambient temperature, whereafter acetlc acid (3 ml) was added. The crystalline preclpitate was collected by filtration, rin~ed with DMF
and water and dried, yielding 2.5 g of the title compound.
M.p. 192-193C. (Compound 1) An additional amount of product precipitated when the fil-trate was evaporated, and the resulting residue was stirred with a mixture of water (100 ml) and ethyl acetate (25 ml).
, f lo 1327798 In a similar manner the following compounds were prepared:
Ethyl imidazo[1,5-a]quinoxaline-3-carboxylate. M.p. 195-196C, from 2-quinoxalinol and ethyl isocyanoacetate. (Compound 2) Isopropyl imidazo[l,5-a]quinoxaline-3-carboxylate. M.p. 205-206C, from 2-quinoxalinol and isopropyl isocyanoacetate.
(Compound 3) Tert-butyl imidazo~l,5-a]quinoxaline-3-carboxylate. M.p.
187-190C, from 2-quinoxalinol and tert-butyl isocyanoace-tate. (Compound 4) Isopropyl 4-methyl-imidazo[1,5-a]quinoxaline-3-carboxylate.
M.p. 182-183C, from 3-methyl-2-quinoxalinol and isopropyl isocyanoacetate. (Compound 5) Tert-butyl 4-methyl-imidazo~1,5-a]qulnoxaline-3-carboxylate.
M.p. 176-177C, from 3-methyl-2-quinoxalinol and tert-butyl isocyanoacetate. (Compound 6) 3-(5-Cyclopropyl-1,2,4-oxadlazol-3-yl)-4-methyl-lmidazo-[1,5-a]quinoxaline. M.p. 165-167C, from 3-methyl-2-quinoxa-linol and 5-cyclopropyl-3-isocyanomethyl-1,2,4-oxadiazole.
(Compound 7) 4-Methyl-3-(S-methyl-1,2,4-oxadiazol-3-yl)-imidazo[1,5-a]-quinoxaline. M.p. 192-193C, from 3-methyl-2-quinoxalinol and 3-isocyanomethyl-5-methyl-1,2,4-oxadiazole. (Compound 8) i 11 ~327798 4-Methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)imidazo[1,5]-quinoxaline (Compound 9) Sodium (0.1 g) was dissolved in dry ethanol (100 ml).
Ethyl 4-methyl-imidazo[1,5-a]quinoxaline-3-carboxylate (1.0 g, 4 mmol), acetamide oxime (1.5 g, 20 mmol) and crushed molecular sieves ~4A, 5 g) were added. After the mixture had been refluxed for 9 h it was cooled to 40C
and dichloromethane (200 ml) was added. The molecular sieves were removed by filtration through a pad of celite, and the filtrate was evaporated in vacuo. The residue was suspended in water (50 ml) and the crystalline precipitate of the title compound was collected by filtration and dried. M.p. 255-256C.
In the same manner the following compounds were prepared:
3-(3-Cyalopropyl-1,2,4-oxadiazol-5-yl)-4-methyl-imldazo-[1,5-a]quinoxallne. M.p. 188-189C, from ethyl 4-methyl-imldazo[1,5-a]quinoxallne-3-carboxylate and cyclopropancar-boxamide oxime. (Compound 10) 3-(3-methyl-1,2,4-oxadiazol-5-yl)-imidazo[1,5-a]~uinoxaline.
M.p. 269-270C, from ethyl imidazo~l,5-a]quinoxaline-3-car-boxylate and acetamlde oxime. (Compound 11) 3-(3-oyclopropyl-1,2,4-oxadiazol-5-yl)-lmidazo~1,5-a]quin-oxaline. M.p. 208-210C, from ethyl imidazo[l,5-a]quinoxa-~ llne-3-oarboxylate and cyclopropancarboxamide oxime.
; (Compound 12) 4-Methyl-3-(3-phenyl-1,2,4-oxadiaxol-5-yl)-imidazo[1,5-a]-guinoxallne. M.p. 272-273C, ~rom ethyl 4-methyl-lm1dazo-. ~
, [1,5-a]quinoxaline-3-carboxylate and benzamide oxime.
(Compound 13) 4-Methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-imidazo[1,5-a]-quinoxaline-5-oxide (Compound 14) 10 4-Methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-imidazo[1,5-a]-quinoxaline (0.36 g, 1.4 mmol) and 55~ 3-chloroper~enzoic acid (0.5 g, 1.6 mmol) was dissolved in dichloromethane (100 ml). After 18 h at room temperature an addidional amount of oxidizing agent (0.5 g) was added, and the solution was heated to reflux for 2 h. Then the reacation mixture was cooled to room temperature and extracted with 10% aqueous potassium carbonate (50 ml). The organic layer was dried over sodium sulphate and evaporated. The residue was suspend-ed in ether, and the title compound was collected by filtra-tion. Purification by column chlomatography (silica gel/-ethyl acetate-methanol 9:1) gave a product with m.p. 239-243C.
In the same manner oxidatlon of 3-(5-cyclopropyl-1,2,4-oxa-25 diazol-3-yl)-4-methyl-lmidazo~1,5-a]quinoxaline gave 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methyl-imidazo[1,5-a]-quinoxaline-5-oxide. M.p. 210-212C. (Compound 15) , :
wherein R' is C1 6-alkyl, which may be straight or branched, C3 7-cyclo-a kyl or phenyl; and R is hydrogen or Cl 6-alkyl; and 5-N-oxides thereof.
The invention also relates to a method of preparing the above mentioned compounds. This method comprises:
a) reacting a compound of formula II
~ ~ R4 (II) wherein R4 has the meaning set forth above and wherein Y is a leaving group, wlth a compound having the formula III
CN - CH2 - R3 (III) wherein R3 has the meaning set forth above, to form a com-pound of the lnvention, or b) reacting a reactive derlvative of a compound havlng the general formula IV
~ ~ C02H (IV) wherein R4 has the meaning set forth above, with a compound having the general formula V
R'- C(=NOH)NH2 (V) wherein R ' has the meaning set forth above to form a compound of the general formula I wherein R is ~0~
~ ~.
wherein R' has the meaning set forth above.
The leaving group, Y, may be any suitable leaving group and, for example, those disclosed in U.S. Patents 4,031,079 or 4,359,420, for example, halogen, alkylthio, e.g., methylthio, aralkylthio, N-nitrosoalkylamino, alkoxy, mercapto, -OP(O)(OR)2 wherein R is lower-alkyl or -OP(O)(NR`R `) where-in R` and R`` each represents lower-alkyl or phenyl, or to-gether with the nitrogen atom to which they are attached re-present a heterocyclic radical such as morpholino, pyrrolidino, piperidino, or methylpiperazino. The reaction is preferably carried out under alkaline conditions, i.e., in the presence of a base, and among bases alkali metal, e.g., potassium or sodium, al~oxldes or hydrldes are pre-ferred. The reactlon is preferably conducted in the presence of an organic solvent which is nonreactive with the reac-tants and products of reaction under the conditlons of reac-tlon, especially an anhydrous solvent and preferably an an-hydrous aprotio solvent such as dlmethylformamlde (DMF) or the like. The temperature range employed may be any range suitable for the reaction to proceed at a reasonable rate and without undue delay or decomposition and a range from a minus forty (-40) degrees Celsius to about room temperature is accordingly usually particularly suitable.
The starting materials may be prepared from commercially available organic compounds and by using well known synthe-tic method8 and as described in Synthesis, Vol. 10, pp.681-682.
4 1327798 ' .
The pharmaceutical properties of the compounds of the inven-tion can be illustrated by determining their capability for displacing radioactive labelled flunitrazepam from benzodi-azepine receptors.
The displacement activity of the compounds of the invention may be found by determining the ED50 value. The ED50 value represents the dose (mg/kg) of a test substance which causes the specific binding of flunitrazepam to benzodiazepine re-ceptors in a living brain to be reduced to 50~ of the con-trol value.
Such an in vivo test is carried out as follows:
Princi~le. Twenty mlnutes after a dose of H-flunitrazepam (3H-FNM) (200 ~Ci/kg, l.v.) the amount of specific 3H-FNM
binding to brain benzodiazepine receptors has reached its maximal value. This specific binding of 3H-FNM can be part-ly or completely prevented by simultaneous or prior adminl-stration of pharmacologically active benzodiazepines and bysome benzodlazepine-like agents (Chang and Snyder, Eur.J.
Pharmacol. 48, 212-218 (1978)).
Test procedure. Suspenslons of test substances (2 mg/ml) are prepared in 5~ Duphasol-X (TM Duphar, castor oil-ethylene oxlde derivative for emulsifying and solubilizing oil and other water-insoluble substances) by sonlficatlon for 10 min using a Bran80n B15 microtip ultrasonifier (setting 7).
Groups of three miae (female, MMR, 18-22 grams) are inJected with the test sUb8tance at 100 mg/kg intraperitoneally. Fif-teen minute9 after test substance administration the mice are challenged with 4 ~Ci intravenously of 3H-FNM (70-90 Ci/mole) ln 200 ~1 physiological saline. ~wenty minutes after 3H-FNM admlnistratlon mlce are sacrificed by decapita-tlon, the forebralns rapldly excised (within 30 sec) andhomogenized in 12 ml of lcecold 25 mM KH2P04, pH 7.1, using an Ultra-Turrax homogenizer fitted with an N 10 shaft. Two .
aliquots of 1 ml are immedlately filtered through Whatman GF/C glassfibre filters and washed with 2 x 5 ml af the above mentioned buffer. The amounts of radioactivity on the filters are determined by conventional scintillation count-ing. One group of untreated mice serves as control. One tothree mice are inJected with 25 ,ug/kg clonazepam i.p. 30 minutes before H-FMM to determine the amount of non-speci-fic H-FMM binding, which should be between 8-15~ of total binding. When doses of 100 mg/kg inhibit more than 50% of specific H-flunitrazepam binding; test substances are admi-nistered in doses, which are factors of 3.16 times lower than 100 mg/kg. The ED50 for a test substance ls defined as that dose which inhibits 50% of specific H-FNM binding.
Specific binding is the amount of binding in controls mlnus the amount binding ln clonazepam-treated mice.
Results. The ED50 value is determined from dose response curves. If only one dose of test substance is administered the ED50 value is calculated as follows, provided that the inhlbltlon of specific binding is within the range of 25-75%:
ED50 ' (admini5tered dose) x mg/kg r CO
_ - 1 ~ Cx where CO is specific blnding ln controls and Cx ls speclfic blnding in mice treated wlth test substance.
Test results obtained by testing some compounds of the in-ventlon will appear from the following table I.
, TABLE 1, CompoundED50 (mg/kg) 8 1.8 7 1.3 3.5 The compound of the invention, together with a conventional adjuvant, carrier, or diluent, and if desired in the form of a pharmaceutically-acceptable acid addltion salt thereof, may be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or fllled capsules, or llquids, such as solutions, suspensions, emulsions, elixirs, or cap-sules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterlle ln~ectable solutlons for parenteral (including subcutaneous) use. Such pharmaceutlcal compositions and unlt dosage forms thereof may comprise conventional ingre-dients in conventional proportions, with or without additio-nal active compounds or principles, and such unit dosage forms may contain any suitable effective central nervous system ailment alleviating amount of the active ingredient commensurate with the intended daily dosage range to be employed. Tablets containlng one (1) milligram of active ingredient or, more broadly, one (1) to thirty (30) milli-grams, per tablet, are aocordlngly sultable representativeunit dosage forms.
The oompounds of this invention can thu~ be used for the formulation of pharmaceutical preparations, e.g., for oral and parenteral administratlon to mammals including humans, ln accordance with conventional methods of galenic pharmacy.
,. ~ .~ .
, . . . .
..
.
.
Conventional excipients are such pharmaceutically acceptable organic or inorganic carrier substances suitable for paren-teral or oral application which do not deleteriously react with the active compound.
Examples of such carriers are water, salt solutions, alco-hols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose and polyvinylpyrrolidone.
The pharmaceutical preparations can be sterilized and mixed, if desired, with auxilliary agents, such as lubricants, pre-1~ servatives, stabilizers, wettlng agents, emulsifiers, saltfor influenclng osmotic pressure, buffers and/or coloring substances and the like, which do not deleteriously react with the active compound.
For parenteral application, particularly suitable are in~ec-table solutions or suspensions, prefarably aqueous solutions with the actlve compound dissolved in polyhydroxylated cas-tor oil.
Ampoules are convenient unit dosage forms.
For oral applicatlon, particularly suitable are tablets, dragees, or capsule~ having talc and/or a carbohydrate car-rler or binder or the like, the carrier preferably being lactose and/or corn starch and/or potato starch. A syrup, elixir or llke can be used when a sweetened vehicle can be employed. Generally, as to broader ranges, the compounds of the lnvention are dlspensed ln unit dosage form comprising 0.05-100 mg in a pharmaceutically-acceptable carrier per unlt dosage.
A typical tablet which may be prepared by conventional tab-letting techniques contains:
Active compound 1.0 mg Lactosum 67.8 mg Ph.Eur.
Avicel~ 31.4 mg Amberlite~ IRP 8~1.0 mg Magnesii stearas 0.25 mg Ph.Eur.
Due to their high degree of affinity for the benzodiazepin receptors, the compounds of the invention are extremely use-ful in the treatment of eentral nervous system ailments or disorders, when administered in an amount effective for the alleviation, amelioration, or elimlnation thereof. The im-15 portant CNS aativity of the compounds of the invention in- -cludes both anticonvulsant and anxiolytic actlvities along with a low toxielty, together presenting a most favorable therapeutie lndex. The eompounds of the invention may accord-ingly be administered to a sub~ect, e.g., a living animal body, includlng a human, in need of the same for the treat-ment, alleviatlon, amelioration, or elimination of an indi-cation, associated with the central nervous system and the socalled benzodiazepin receptors, which re~ulres sueh psyeho-pharmaeeutieal treatment, e.g., especlally eonvulsion and/or anxiety states, if desired in the form of a pharmaeeutieally-aeeeptable aoid addition salt thereof (such as the hydro-bromide, hydroehloride, or sulfate, in any event prepared in the usual or eonventional manner, e.g., evaporation to dryness of the free base in solution together with the aeid), ordlnarlly eoneurrently, slmultaneously, or together with a pharmaeeutieally-aeceptable earrier or diluent, espeelally and preferably in the form of a pharmaceutical composition thereof, whether by oral, reetal, or parenteral (lneludlng subeutaneous) route, ln an effective psychopharmaceutieal eentral nervous system allment allevlating amount, e.g., an antleonvulsant and/or anxiolytie amount, and in any event ~' an amount which is effective for the alleviation of such a central nervous system ailment due to their benzodiazepine receptor affinity. Suitable dosage ranges are 1-200 milli-grams daily, 1-100 milligrams daily, and especlally 1-30 milligrams daily, depending as usual upon the exact mode of administration, form in which administered, the indication toward which the administration is directed, the sub~ect involved and the body weight of the subject involved, and ; the preference and experience of the physician or veteri-narian in charge.
The invention will now be described in further detail with reference to the following examples:
Ethyl 4-methyl-lmidazo[1,5-a]quinoxaline-3-carboxylate 3-Methyl-2-~ulnoxalinol (2.84 g, 18 mmol) was dlssolved ln dry DMF (40 ml) and charged wlth sodium hydride (55~ oil dispersion, 1.0 g, 23 mmol). The resulting solution was cooled under nitrogen to -20C, whereafter chlorodiethyl-phosphate (3.3 ml, 23 mmol) was added. The reaction mixturewas allowed to reach room temperature, and was then added a -30C cold solution of ethyl isocyanoacetate (2.6 g, 23 mmol) and potassium t-butoxide (2.6 g, 23 mmol) in dry DMF (25 ml).
The mixture was stirred for 45 min. at ambient temperature, whereafter acetlc acid (3 ml) was added. The crystalline preclpitate was collected by filtration, rin~ed with DMF
and water and dried, yielding 2.5 g of the title compound.
M.p. 192-193C. (Compound 1) An additional amount of product precipitated when the fil-trate was evaporated, and the resulting residue was stirred with a mixture of water (100 ml) and ethyl acetate (25 ml).
, f lo 1327798 In a similar manner the following compounds were prepared:
Ethyl imidazo[1,5-a]quinoxaline-3-carboxylate. M.p. 195-196C, from 2-quinoxalinol and ethyl isocyanoacetate. (Compound 2) Isopropyl imidazo[l,5-a]quinoxaline-3-carboxylate. M.p. 205-206C, from 2-quinoxalinol and isopropyl isocyanoacetate.
(Compound 3) Tert-butyl imidazo~l,5-a]quinoxaline-3-carboxylate. M.p.
187-190C, from 2-quinoxalinol and tert-butyl isocyanoace-tate. (Compound 4) Isopropyl 4-methyl-imidazo[1,5-a]quinoxaline-3-carboxylate.
M.p. 182-183C, from 3-methyl-2-quinoxalinol and isopropyl isocyanoacetate. (Compound 5) Tert-butyl 4-methyl-imidazo~1,5-a]qulnoxaline-3-carboxylate.
M.p. 176-177C, from 3-methyl-2-quinoxalinol and tert-butyl isocyanoacetate. (Compound 6) 3-(5-Cyclopropyl-1,2,4-oxadlazol-3-yl)-4-methyl-lmidazo-[1,5-a]quinoxaline. M.p. 165-167C, from 3-methyl-2-quinoxa-linol and 5-cyclopropyl-3-isocyanomethyl-1,2,4-oxadiazole.
(Compound 7) 4-Methyl-3-(S-methyl-1,2,4-oxadiazol-3-yl)-imidazo[1,5-a]-quinoxaline. M.p. 192-193C, from 3-methyl-2-quinoxalinol and 3-isocyanomethyl-5-methyl-1,2,4-oxadiazole. (Compound 8) i 11 ~327798 4-Methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)imidazo[1,5]-quinoxaline (Compound 9) Sodium (0.1 g) was dissolved in dry ethanol (100 ml).
Ethyl 4-methyl-imidazo[1,5-a]quinoxaline-3-carboxylate (1.0 g, 4 mmol), acetamide oxime (1.5 g, 20 mmol) and crushed molecular sieves ~4A, 5 g) were added. After the mixture had been refluxed for 9 h it was cooled to 40C
and dichloromethane (200 ml) was added. The molecular sieves were removed by filtration through a pad of celite, and the filtrate was evaporated in vacuo. The residue was suspended in water (50 ml) and the crystalline precipitate of the title compound was collected by filtration and dried. M.p. 255-256C.
In the same manner the following compounds were prepared:
3-(3-Cyalopropyl-1,2,4-oxadiazol-5-yl)-4-methyl-imldazo-[1,5-a]quinoxallne. M.p. 188-189C, from ethyl 4-methyl-imldazo[1,5-a]quinoxallne-3-carboxylate and cyclopropancar-boxamide oxime. (Compound 10) 3-(3-methyl-1,2,4-oxadiazol-5-yl)-imidazo[1,5-a]~uinoxaline.
M.p. 269-270C, from ethyl imidazo~l,5-a]quinoxaline-3-car-boxylate and acetamlde oxime. (Compound 11) 3-(3-oyclopropyl-1,2,4-oxadiazol-5-yl)-lmidazo~1,5-a]quin-oxaline. M.p. 208-210C, from ethyl imidazo[l,5-a]quinoxa-~ llne-3-oarboxylate and cyclopropancarboxamide oxime.
; (Compound 12) 4-Methyl-3-(3-phenyl-1,2,4-oxadiaxol-5-yl)-imidazo[1,5-a]-guinoxallne. M.p. 272-273C, ~rom ethyl 4-methyl-lm1dazo-. ~
, [1,5-a]quinoxaline-3-carboxylate and benzamide oxime.
(Compound 13) 4-Methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-imidazo[1,5-a]-quinoxaline-5-oxide (Compound 14) 10 4-Methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-imidazo[1,5-a]-quinoxaline (0.36 g, 1.4 mmol) and 55~ 3-chloroper~enzoic acid (0.5 g, 1.6 mmol) was dissolved in dichloromethane (100 ml). After 18 h at room temperature an addidional amount of oxidizing agent (0.5 g) was added, and the solution was heated to reflux for 2 h. Then the reacation mixture was cooled to room temperature and extracted with 10% aqueous potassium carbonate (50 ml). The organic layer was dried over sodium sulphate and evaporated. The residue was suspend-ed in ether, and the title compound was collected by filtra-tion. Purification by column chlomatography (silica gel/-ethyl acetate-methanol 9:1) gave a product with m.p. 239-243C.
In the same manner oxidatlon of 3-(5-cyclopropyl-1,2,4-oxa-25 diazol-3-yl)-4-methyl-lmidazo~1,5-a]quinoxaline gave 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methyl-imidazo[1,5-a]-quinoxaline-5-oxide. M.p. 210-212C. (Compound 15) , :
Claims (9)
1. Imidazoguinoxaline compounds selected from those having the formula I
(I) (I) wherein R3 is or , wherein R' is C1-6-alkyl, which may be straight or branched, C3-7-cyclo-alkyl,or phenyl: and R4 is hydrogen or C1-6-alkyl; and 5-N-oxides thereof.
(I) (I) wherein R3 is or , wherein R' is C1-6-alkyl, which may be straight or branched, C3-7-cyclo-alkyl,or phenyl: and R4 is hydrogen or C1-6-alkyl; and 5-N-oxides thereof.
2. A compound of claim 1 whlch is 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methyl-imidazo[1,5-a]quinoxaline.
3. A compound of claim 1 which is 4-methyl-3-(5-methyl-1,2,4-oxadiazol-3-yl)-imidazo[1,5-a]guinoxaline.
4. A pharmaceutical composition sultable for use in the treatment of a central nervous system ailment comprising an amount of a compound of claim 1 which is effective for the alleviation of such disorder together with a pharmaceutically-acceptable carrier or diluent.
5. A pharmaceutical composition according to claim 4 wherein it is in the form af an oral dosage unit containing 1-100 mg of the active compound.
6. The use of a compound of Claim 1 for the preparation of a pharmaceutical composition useful for treating a central nervous system ailment.
7. A method of preparing a pharmaceutical composition useful for treating a central nervous system ailment in a subject in need of such treatment comprising the step of admixing an amount of a compound of Claim 1 which is effective for the alleviation of such ailment together with a pharmaceutically-acceptable carrier or diluent.
8. A method of preparing a compound according to claim 1, which comprises the following:
a) reacting a compound of formula II
(II) wherein R4 has the meaning set forth above and wherein Y is a leaving group, with a compound having the formula III
CN - CH2 - R3 (III) wherein R3 has the meaning set forth in Claim 1, to form a compound of Claim 1, or b) reacting a reactive carboxyl derivative of a compound having the general formula IV
(IV) wherein R4 has the meaning set forth above, with a compound having the general formula V
R'- C(=NOH)NH2 (V) wherein R' has the meaning set forth above to form a com-pound of the general formula I wherein R3 is wherein R' has the meaning set forth above.
a) reacting a compound of formula II
(II) wherein R4 has the meaning set forth above and wherein Y is a leaving group, with a compound having the formula III
CN - CH2 - R3 (III) wherein R3 has the meaning set forth in Claim 1, to form a compound of Claim 1, or b) reacting a reactive carboxyl derivative of a compound having the general formula IV
(IV) wherein R4 has the meaning set forth above, with a compound having the general formula V
R'- C(=NOH)NH2 (V) wherein R' has the meaning set forth above to form a com-pound of the general formula I wherein R3 is wherein R' has the meaning set forth above.
9. Method of Claim 8, wherein the reaction a) is carried out under alkaline conditions.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DKDK3220/88 | 1988-06-14 | ||
| DK322088A DK161148C (en) | 1988-06-14 | 1988-06-14 | IMIDAZOQUINOXAL COMPOUNDS, PROCEDURES FOR PREPARING THEREOF, AND PHARMACEUTICAL PREPARATIONS CONTAINING THE COMPOUNDS |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1327798C true CA1327798C (en) | 1994-03-15 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000602682A Expired - Fee Related CA1327798C (en) | 1988-06-14 | 1989-06-13 | Imidazoquinoxaline compounds and their preparation and use |
Country Status (18)
| Country | Link |
|---|---|
| US (1) | US5034530A (en) |
| EP (1) | EP0347094B1 (en) |
| JP (1) | JPH0236184A (en) |
| KR (1) | KR910000665A (en) |
| AT (1) | ATE111100T1 (en) |
| AU (1) | AU618366B2 (en) |
| CA (1) | CA1327798C (en) |
| DE (1) | DE68918003T2 (en) |
| DK (1) | DK161148C (en) |
| ES (1) | ES2060769T3 (en) |
| FI (1) | FI92204C (en) |
| IE (1) | IE69963B1 (en) |
| IL (1) | IL90543A0 (en) |
| NO (1) | NO170806C (en) |
| NZ (1) | NZ229499A (en) |
| PH (1) | PH26337A (en) |
| PT (1) | PT90865B (en) |
| ZA (1) | ZA894430B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK160876C (en) * | 1987-12-08 | 1991-10-14 | Novo Nordisk As | IMIDAZOQUINOXAL COMPOUNDS, PROCEDURES FOR THEIR PREPARATION, APPLICATION OF THE COMPOUNDS AND PHARMACEUTICAL PREPARATIONS CONTAINING THE COMPOUNDS |
| US5371080A (en) * | 1990-06-22 | 1994-12-06 | Novo Nordisk A/S | Imidazoquinazoline compounds and their use |
| DK151890D0 (en) * | 1990-06-22 | 1990-06-22 | Ferrosan As | HETEROCYCLIC RELATIONSHIPS OF THEIR PREPARATION AND USE |
| US5276028A (en) * | 1990-06-22 | 1994-01-04 | Nordisk A/S | Imidazoquinoxaline compounds |
| US5153196A (en) * | 1991-06-05 | 1992-10-06 | Eli Lilly And Company | Excitatory amino acid receptor antagonists and methods for the use thereof |
| KR100207360B1 (en) * | 1991-06-14 | 1999-07-15 | 돈 더블유. 슈미츠 | Imidazon (1,5-a) quinoxalines |
| US6635626B1 (en) | 1997-08-25 | 2003-10-21 | Bristol-Myers Squibb Co. | Imidazoquinoxaline protein tyrosine kinase inhibitors |
| US6235740B1 (en) | 1997-08-25 | 2001-05-22 | Bristol-Myers Squibb Co. | Imidazoquinoxaline protein tyrosine kinase inhibitors |
| WO1999045009A1 (en) * | 1998-03-04 | 1999-09-10 | Bristol-Myers Squibb Company | Heterocyclo-substituted imidazopyrazine protein tyrosine kinase inhibitors |
| US20040180898A1 (en) * | 2003-03-03 | 2004-09-16 | Bang-Chi Chen | Processes for preparing imidazoquinoxalinones, heterocyclic-substituted imidazopyrazinones, imidazoquinoxalines and heterocyclic-substituted imidazopyrazines |
| WO2009070584A1 (en) | 2007-11-30 | 2009-06-04 | Wyeth | Aryl and heteroaryl fused imidazo[1,5-a]pyrazines as inhibitors of phosphodiesterase 10 |
| CA2706986A1 (en) * | 2007-11-30 | 2009-06-04 | Elbion Gmbh | Aryl and heteroaryl fused imidazo (1,5-a) pyrazines as inhibitors of phosphodiesterase 10 |
| WO2010138833A1 (en) * | 2009-05-29 | 2010-12-02 | Wyeth | SUBSTITUTED IMIDAZO[1,5-a]QUINOXALINES AS INHIBITORS OF PHOSPHODIESTERASE 10 |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4440929A (en) * | 1981-07-16 | 1984-04-03 | Usv Pharmaceutical Corporation | Imidazoquinoxaline compounds |
| DK476885D0 (en) * | 1985-10-17 | 1985-10-17 | Ferrosan As | HETEROCYCLIC RELATIONS AND PROCEDURES FOR PREPARING IT |
| EP0221699B1 (en) * | 1985-10-19 | 1990-01-10 | Beecham Group Plc | Composition for the treatment of infections |
| DK155524C (en) * | 1987-03-18 | 1989-09-11 | Ferrosan As | CONDENSED IMIDAZOLD DERIVATIVES AND PHARMACEUTICAL PREPARATIONS CONTAINING THESE |
-
1988
- 1988-06-14 DK DK322088A patent/DK161148C/en not_active IP Right Cessation
-
1989
- 1989-06-06 IL IL90543A patent/IL90543A0/en not_active IP Right Cessation
- 1989-06-07 ES ES89305728T patent/ES2060769T3/en not_active Expired - Lifetime
- 1989-06-07 EP EP89305728A patent/EP0347094B1/en not_active Expired - Lifetime
- 1989-06-07 AT AT89305728T patent/ATE111100T1/en not_active IP Right Cessation
- 1989-06-07 DE DE68918003T patent/DE68918003T2/en not_active Expired - Fee Related
- 1989-06-08 PH PH38760A patent/PH26337A/en unknown
- 1989-06-08 US US07/363,585 patent/US5034530A/en not_active Expired - Fee Related
- 1989-06-12 ZA ZA894430A patent/ZA894430B/en unknown
- 1989-06-12 NZ NZ229499A patent/NZ229499A/en unknown
- 1989-06-13 JP JP1148537A patent/JPH0236184A/en active Pending
- 1989-06-13 NO NO892456A patent/NO170806C/en unknown
- 1989-06-13 CA CA000602682A patent/CA1327798C/en not_active Expired - Fee Related
- 1989-06-13 IE IE189289A patent/IE69963B1/en not_active IP Right Cessation
- 1989-06-13 AU AU36244/89A patent/AU618366B2/en not_active Ceased
- 1989-06-14 KR KR1019890008164A patent/KR910000665A/en not_active Application Discontinuation
- 1989-06-14 FI FI892908A patent/FI92204C/en not_active IP Right Cessation
- 1989-06-14 PT PT90865A patent/PT90865B/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| DK322088A (en) | 1990-03-27 |
| ATE111100T1 (en) | 1994-09-15 |
| PH26337A (en) | 1992-04-29 |
| EP0347094B1 (en) | 1994-09-07 |
| ZA894430B (en) | 1990-02-28 |
| AU618366B2 (en) | 1991-12-19 |
| DE68918003T2 (en) | 1995-01-05 |
| FI92204B (en) | 1994-06-30 |
| NO892456D0 (en) | 1989-06-13 |
| NZ229499A (en) | 1991-04-26 |
| NO892456L (en) | 1989-12-15 |
| DK161148B (en) | 1991-06-03 |
| EP0347094A1 (en) | 1989-12-20 |
| FI92204C (en) | 1994-10-10 |
| ES2060769T3 (en) | 1994-12-01 |
| DK322088D0 (en) | 1988-06-14 |
| KR910000665A (en) | 1991-01-30 |
| IE891892L (en) | 1989-12-14 |
| PT90865B (en) | 1994-11-30 |
| AU3624489A (en) | 1989-12-21 |
| IL90543A0 (en) | 1990-01-18 |
| FI892908A0 (en) | 1989-06-14 |
| PT90865A (en) | 1989-12-29 |
| JPH0236184A (en) | 1990-02-06 |
| NO170806B (en) | 1992-08-31 |
| DE68918003D1 (en) | 1994-10-13 |
| FI892908A (en) | 1989-12-15 |
| US5034530A (en) | 1991-07-23 |
| IE69963B1 (en) | 1996-10-16 |
| NO170806C (en) | 1992-12-09 |
| DK161148C (en) | 1991-11-18 |
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